Among the many undesirable effects of systemic cancer is metastatic spread to the brain, with subsequent deleterious effects on many critical functions controlled by this organ. Brain metastasis (BMs) represents a major health care problem. Common sources of brain metastases are lung, breast, renal and colorectal carcinoma, and malignant melanoma, and it has been estimated that some patients with these cancers may develop brain metastasis in the course of their disease [Langley R R, Fidler I J. International Journal of Cancer. 2011; 128(11):2527-2535)]. The incidence of brain metastases from ovarian carcinoma (7/335, 2.1%) was higher than those from uterine corpus carcinoma (4/556, 0.7%), uterine cervix carcinoma (7/1716, 0.4%), and other female genital tract malignancies combined (vagina, vulva, and fallopian tube carcinoma) (0/122, 0%) [Ogawa K, et al. Neurologia Medico-Chirurgica. 2008; 48(2):57-62]. The medians of the survival times after diagnosis of brain metastases ranged from 1 to 28 months with a median of the medians of 6.4 months. Thus, overall, the survival of patients after diagnosis of brain metastases from ovarian carcinoma is poor. [Ettie Piura and Benjamin Piura: Oncol. 2011; 2011: 527153) 527453]
Metastatic tumors involving the brain overshadow primary brain neoplasms in frequency and are an are important complications in the overall management of a large number of cancers. Among the many primary malignancies, lung, breast, melanoma, renal, and colon cancers are the main causes brain metastases (whereas other cancers such as prostate, liver, bladder, pancreatic, and uterine have a lower propensity to seed the brain). Brain metastases are associated with poor prognosis as well as significant morbidity and treatment is palliative in most cases. Irrespective of the location, origin, and clinical presentation of brain metastases, current therapeutic efforts remain limited to multimodal approaches consisting of symptomatic therapy with corticosteroids, whole brain radiotherapy (WBRT), stereotactic radiosurgery and/or surgery which lead to a median survival of 3 to 6 months. Until today, no effective measures are available to reliably prevent this event. Thus, intense vigilance for relevant symptoms and early confirmation of brain metastases is critical to enable intervention and to minimize irreversible damage of the nervous system. The lack of clinically or biologically-based targeted therapies is mainly due to the few conceptual frameworks and even fewer in vitro and in vivo model systems for studying brain metastases.
The brain is one of the most common sites for lung adenocarcinoma metastasis [Sperduto P W, et al. J Clin Oncol 2012; 30:419-25]. These patients have poor median survival, and more effective therapies are urgently required. Since traditional chemotherapy is less effective against metastatic brain tumors, radiotherapy remains the main therapeutic or palliative option for inoperable central nervous system (CNS) disease. Radiotherapy supplemented with steroids has yielded responses rates of 50-75% for intracranial lesions, providing rapid attenuation of neurologic symptoms and improvement of performance status However, brain metastases still herald a poor prognosis with a median survival of less than six months. Patients with advanced NSCLC (non-small-cell lung carcinoma) relapsing after chemotherapy generally have a poor prognosis, particularly in the case of patients having brain metastases.
Brain metastases are a common problem in patients with metastatic NSCLC. About 7%-10% of NSCLC patients present with brain metastases at the time of initial diagnosis, and a significant number of patients develop brain metastases at some point during their illness.
Medical treatment directed at cancer cells that have seeded into the brain is ineffective. The failure of chemical therapy has always been attributed to an intact Brain Blood Barrier and the acquisition of drug resistance by the cancer cells.
Standard treatment for NSCLC's brain metastases is Whole brain radiation therapy (WBRT). With this treatment (treatment schedule of 30 Gy), median survival is 3-6 months depending on number of lesions, their radiosensitivity, and the status of systemic disease (Tse V, Brain Metastasis Treatment & Management-Medscape Updated: Apr. 16, 2014).
More aggressive treatment with surgery or stereotactic radiotherapy is possible only in a subset of patients (these modalities have many limitations depending on the location and characteristics of the tumor). The role of systemic treatment in this setting remains controversial. Data from large series of patients (treated for example with gefitinib, see below) are lacking because the presence of brain metastases disease has mostly been considered among exclusion criteria, and, usually, data on brain metastases are not analyzed separately.
Classical medical treatment directed at cancer cells that have seeded into the brain are mostly ineffective. The failure of chemical therapy has always been attributed to an intact blood brain barrier (BBB) and by the acquisition of drug resistance by cancer cells. Most tumors that metastasize to the brain are not chemosensitive. A variety of chemotherapeutic agents have been used to treat brain metastasis from lung, breast, and melanoma, including cisplatin, cyclophosphamide, etoposide, teniposide, mitomycin, irinotecan, vinorelbine, etoposide, ifosfamide, temozolomide, fluorouracil (5FU), and prednisone. In most cases, 2-3 of these agents are used in combination and in conjunction with WBRT. Unfortunately, the outcome with this approach is not promising.
The advent in small-molecule tyrosine kinase inhibitors (TKI has helped to transform the management of brain metastasis. Gefitinib and erlotinib, epidermal growth factor receptor (EGFR) TKI, have shown promising results in treating NSCLC that metastasize to the brain. But these treatments are mainly efficient with patients with the EGFR mutation (Ceresoli G L et al. (2004) Ann Oncol. 15(7): 1042-7.
Monoclonal antibodies such as trastuzumab have been used in treating metastatic breast cancer. The latter, however, is not that effective in crossing the BBB and results in relapse within the central nervous system.
Therefore, there is still a strong need of therapy in order to treat brain metastases and offer a longer survival than the usual 3 to 6 months.